PAM expression in pituitary neuroendocrine tumors (PitNETs)

Birtolo Maria Francesca; Bertrand Baussart; Nesrine Benanteur; Anne Jouinot; Adrian Daly; Andrea Lania; Jerome Bertherat; Constantine Stratakis; Guillaume Assie; Chiara Villa; Giampaolo Trivellin

doi:10.1530/endoabs.99.EP401

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Endocrine Abstracts (2024) 99 EP401 | DOI: 10.1530/endoabs.99.EP401

ECE2024 Eposter Presentations Pituitary and Neuroendocrinology (214 abstracts)

PAM expression in pituitary neuroendocrine tumors (PitNETs)

Maria Francesca Birtolo ^1,2 , Bertrand Baussart ^1,3 , Nesrine Benanteur ¹ , Anne Jouinot ^1,4 , Adrian Daly ⁵ , Andrea Lania ^2,6 , Jerome Bertherat ^1,4 , Constantine Stratakis ⁷ , Guillaume Assié ^1,4 , Chiara Villa ^1,8 & Giampaolo Trivellin ²

Err

Author affiliations

¹INSERM U1016, Université Paris Cité, CNRS, Inserm, Institut Cochin, Genomics and signaling of endocrine tumors, Paris, France;²Humanitas University, Department of Biomedical Sciences, Pieve Emanuele (MI), Italy;³Hôpital Universitaire Pitié-Salpêtrière, APHP, Sorbonne Université, Department of Neurosurgery, Paris, France;⁴Métabolisme Et Cancer, CHU Cochin, APHP, Université Paris Cité, Département Endocrinologie, Paris, France;⁵Centre Hospitalier Universitaire de Liège, University of Liège, Domaine Universitaire du Sart-Tilman, Department of Endocrinology, Liège, Belgium;⁶IRCCS Humanitas Research Hospital, Endocrinology, Diabetology and Andrology United, Milan, Italy;⁷IMBB, FORTH, Heraklion, Greece & NICHD, NIH, Human Genetics & Precision Medicine, Bethesda, United States;⁸Hôpital Universitaire Pitié-Salpêtrière, APHP, Sorbonne Université, Department of Neuropathology, Paris, France

PAM encodes a multifunctional protein recognized as an important regulator of hormone amidation and secretion. Since PAM germline mutations have been recently identified in patients with PitNETs, it has been proposed as a candidate gene associated with pituitary hypersecretion.

Aim: To characterize PAM expression in a large cohort of PitNETs through immunohistochemistry and transcriptome analysis (RNA sequencing).

Methods: Immunohistochemistry analysis was performed on FFPE samples from normal pituitary, 102 PitNETs of all hystotypes (16 functioning and 13 silent corticotrophs, 19 somatotrophs, 20 gonadotrophs, 8 null-cell, 19 prolactinomas, and 7 thyrotrophs) and 5 PitNETs with recognized PAM variants. PAM immunoreactivity was graded considering the percentage of positive cells and the staining intensity (scored from 0 to 3). The final score was obtained as follow: score = (%x0)+(%x1)+(%x2)+(%x3). PAM expression was assessed through transcriptome analysis on a previously reported dataset of 134 PitNETs (Neou M, Assié G. Cancer Cell. 2020).

Results: PAM immunostaining was positive almost in all samples with variable patterns of expression. However, the immunohistochemistry score was lower in corticotroph tumors with overt Cushing disease compared to the other groups (Kruskal-Wallis, P=3.69e-05). Transcriptome analysis confirmed this finding (Kruskal-Wallis, P=3.888e-10). Interestingly we found weak and negative staining for PAM in 5 patients (2 acromegalic and 3 with overt Cushing disease) in whom PAM variants have recently been identified (Trivellin G, Stratakis CA. Front Endocrinol. 2023).

Conclusion: Our preliminary results add to the characterization of PAM function in PitNETs. A reduced expression in corticotroph PitNETs with overt Cushing disease opens new insights into the pathogenesis of -and secretion by corticotroph tumor cells.